1. Field of the Invention
This invention is related to 2,3-quinoxalinediones having a N-substituted azacycloalkyl ring fused with the quinoxaline system. The N-substituted azacycloalkyl ring fused 2,3-quinoxalinediones are active as excitatory amino acid receptor antagonists acting at glutamate receptors, including either or both N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors such as the .alpha.-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and the kainate receptor. The invention also relates to the use of those quinoxalinediones as neuroprotective agents for treating conditions such as cerebral ischemia or cerebral infarction resulting from a range of phenomena, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma, as well as to treat chronic neurodegenerative disorders such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease and as anticonvulsants. The compounds of the present invention may also be useful in the treatment of schizophrenia, epilepsy, anxiety, pain and drug addiction.
2. Related Background Art
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA) receptor, the .alpha.-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and the kainate receptor. AMPA/kainate receptors may be referred to jointly as non-NMDA receptors. This excitotoxic action is considered responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease and Huntington's Disease. Several classes of quinoxalinedione derivatives have been disclosed as glutamate (EAA) receptor antagonists. For example, U.S. Pat. No. 4,889,855, generically discloses compounds of the formulae: ##STR2##
wherein R.sub.1, R.sub.2 and R.sub.3 are independently H, halogen, CN, NH.sub.2,NO.sub.2,SO.sub.3 H, SO.sub.2 NH.sub.2,and CONH.sub.2. This reference specifically discloses 6-amino, 6-cyano, 5-carbamoyl, 6-nitro and 5,6-dinitro-7,8,9,10-tetrahydro-2,3-dihydroxybenzo(f)quinoxalines. The reference, however, does not disclose any compounds with an azacycloalkyl fused ring, let alone an N-substituted ring. Nor does the reference disclose or suggest any methods which would allow the preparation of N-substituted azacycloalkyl ring fused compounds. U.S. Pat. No. 5,081,123 and U.S. Pat. No. 5,308,845, describe similar structures except that there is respectively a hydroxy or alkoxy function at the nitrogen on the quinoxalinedione skeleton. Again, however, these references do not suggest or illustrate any examples of N-substituted fused azacycloalkylquinoxalinediones.
Having both NMDA and non-NMDA antagonist properties in a single entity may provide a superior pharmacological profile. Combinations of NMDA and non-NMDA receptor antagonists have shown synergistic activity in focal and global ischemia [K. Lippert, M. Welsch and J. Krieglstein, Eur. J. Pharmacol. 253 (3), 207-13 (1994)], as anticonvulsants [W. Loescher, C. Rundfelt, D. Hoenack, Eur. J. Neurosci. 5 (11), 1545-50 (1993)], and in protection of neuronal degeneration in retina [J. Mosinger, M. Price, H. Bai, H. Xiao, D. Wozniak and J. Olney, Exp. Neurol. 113, 10-17 (1991).
Among excitatory amino acid receptor antagonists recognized for usefulness in the treatment of disorders are those that block AMPA receptors [C. F. Bigge and T. C. Malone, Curr. Opin. Ther. Pat., 951 (1993); M. A. Rogawski, TiPS 14, 325 (1993)]. AMPA receptor antagonists have prevented neuronal injury in several models of global cerebral ischemia [H. Li and A. M. Buchan, J. Cerebr. Blood Flow Metab. 13, 933 (1993); B. Nellgard and T. Wieloch, J. Cerebr. Blood Flow Metab. 12, 2 (1992)] and focal cerebral ischemia [R. Bullock, D. I. Graham, S. Swanson, J. McCulloch, J. Cerebr. Blood Flow Metab. 14, 466 (1994); D. Xue, Z. -G. Huang, K. Barnes, H. J. Lesiuk, K. E. Smith, A. M. Buchan, J. Cerebr. Blood Flow Metab. 14, 251 (1994)]. AMPA antagonists have also shown efficacy in models for analgesia [X. -J. Xu, J. -X Hao, A. Seiger, Z. Wiesenfeld-Hallin, J. Pharmacol. Exp. Ther. 267, 140 (1993)], and epilepsy [T. Namba, K. Morimoto, K. Sato, N. Yamada, S. Kuroda, Brain Res. 638, 36 (1994); S. E. Brown, J. McCulloch, Brain Res. 641, 10 (1994); S. I. Yamaguchi, S. D. Donevan, M. A. Rogawski, Epilepsy Res. 15, 179 (1993); S. E. Smith, N. Durmuller, B. S. Meldrum, Eur. J. Pharmacol. 201, 179 (1991)]. AMPA receptor antagonists have also demonstrated promise in chronic neurodegenerative disorders such as Parkinsonism. [T. Klockgether, L. Turski, T. Honore, Z. Zhang, D. M. Gash, R. Kurlan, J. T. Greenamyre, Ann. Neurol., 34(4), 585-593 (1993)].
Excitatory amino acid receptor antagonists that block NMDA receptors are also recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's disease [T. Klockgether, L. Turski, Ann. Neurol. 34, 585-593 (1993)], human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease [P. T. Francis, N. R. Sims, A. W. Procter, D. M. Bowen, J. Neurochem. 60 (5), 1589-1604 (1993)] and Huntington's disease. [See S. Lipton, TINS 16 (12), 527-532 (1993); S. A. Lipton, P. A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 (1994); and C. F. Bigge, Biochem. Pharmacol. 45, 1547-1561 (1993) and references cited therein.]. NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A).
Copending U.S. patent application Ser. No. 08/124,770 discloses glutamate receptor antagonist quinoxalinedione derivatives represented by the formula: ##STR3##
wherein A is a 5 to 7 atom containing ring having a nitrogen which may be substituted by hydrogen, alkyl or CH.sub.2 CH.sub.2 OH. This application does not disclose or suggest compounds having different nitrogen substituents, or the requisite methodology to prepare the same.
An object of this invention is to provide novel N-substituted azacycloalkyl ring fused 2,3-quinoxalinediones which function as either or both NDMA antagonists or non-NMDA antagonists.
A further object of this invention is to provide a pharmaceutical composition containing an effective amount of the N-substituted azacycloalkyl ring fused 2,3-quinoxalinediones to treat cerebrovascular disorders responsive to blocking any or all of NMDA receptors, AMPA receptors and kainate-receptors.
Another object of this invention is to provide a method of treating disorders responsive to the antagonism of glutamate or aspartate receptors in a human by administering a pharmaceutically effective amount of the N-substituted azacycloalkyl ring fused 2,3-quinoxalinediones of this invention.
Another object of this invention is to provide novel methods of preparing N-substituted azacycloalkyl ring fused 2,3-quinoxalinediones.
A further object of this invention is directed to novel intermediates of the N-substituted azacycloalkyl ring fused 2,3-quinoxalinediones of this invention.